Abstract
The role of nitric oxide in the inhibition of the cytochrome P450 system produced by interferon-γ in human hepatocytes has been examined. Nitric oxide exogenously released from S-nitroso-N-acetylpenicillamine produced a dose-dependent decrease in cytochrome P4501A2 activity, assessed as 7-ethoxy resorufin O-deethylation. After 24 hr of treatment with 300 U/ml interferon-γ, a rise in nitric oxide release (200% over control cells) and a parallel inhibition in 7-ethoxyresorufin O-deethylase activity (50% of control) were observed in human hepatocytes. This inhibition was concentration-dependently prevented by NG-monomethyl-l-arginine, a competitive inhibitor of nitric oxide biosynthesis. Comparable results were observed for cytochrome P4502A6 (7-coumarin hydroxylation), 2B6 (7-benzoxyresorufin O-dealkylation) and 3A4 (testosterone 6β-hydroxylation) activities. Decreases in CYP1A2 activity found after exposure of 3-methylcholanthrene-treated hepatocytes to interferon-γ were also reversed in the presence of NG-monomethyl-l-arginine. Down-regulation of cytochrome P4501A2 and 3A4 expression by interferon-γ was observed in parallel. This study suggests that at least some of the interferon-γ effects on human hepatocyte cytochrome P450 isoenzymes are mediated by nitric oxide biosynthesis.
Footnotes
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Send reprint requests to: Dr. M. JoséGómez-Lechón, Unidad de Hepatologı́a Experimental, Centro de Investigación, Hospital Universitario La Fe, Avda. Campanar 21, 46009-Valencia, Spain.
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↵1 This work was supported by the European Union (Biomed I, Project Nr. BMH1–1097 and AIR, Project Nr. CT93–0860), the Spanish Fondo de Investigaciones Sanitarias (Project Nr. 94/1084) and The ALIVE Foundation.
- Abbreviations:
- BROD
- 7-benzoxyresorufin O-dealkylase
- CH
- coumarin 7-hydroxylase
- CYP
- cytochrome P450
- EROD
- 7-ethoxyresorufin O-deethylase
- IFN
- interferon
- MC
- 3-methylcholanthrene
- NMA
- NG-monomethyl-l-arginine
- NO
- nitric oxide
- PROD
- 7-pentoxyresorufin O-depentylase
- RT-PCR
- reverse transcriptase-polymerase chain reaction
- SNAP
- S-nitroso-N-acetylpenicillamine
- 6β-OHT
- testosterone 6β-hydroxylase
- Received June 5, 1996.
- Accepted December 5, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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